title: Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors.
abstract: OBJECTIVE
  E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors.
  
  
  METHODS
  In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis.
  
  
  RESULTS
  Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, C(max) and area under the plasma concentration-time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(-) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect.
  
  
  CONCLUSIONS
  E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors.
authors.affiliation: Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Taizo
authors.initials: T
authors.lastname: Hirata
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koyama
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D054377:Chemokine CXCL12 / Q000097:blood; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000378:metabolism; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000097:blood; D011804:Quinolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013234:Stem Cells / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D054377:Chemokine CXCL12; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D019009:Proto-Oncogene Proteins c-kit; C531958:lenvatinib